Abstract: Vaccines against devastating infectious diseases represent some of mankind's greatest medical breakthroughs. The underlying principle of vaccines is the establishment of immunity using attenuated or inactivated vectors that mimic the natural pathogen without causing the systemic damage a live infection can trigger. Thus the prerequisite for all successful vaccines to date is that the human immune system must be inherently capable of eventually generating adaptive immunity when faced with the natural live infection. In cases like polio, the damage achieved before adaptive immunity can control the natural virus is unacceptable; nevertheless, lasting immunity is ultimately achieved and protects against subsequent infections. Currently, however, many of the most problematic infectious diseases worldwide cannot be effectively controlled by the human immune system and do not elicit lasting immunity against re-infection. For example, by virtue of its mutability, HIV establishes chronic infections that cannot be cleared and are ineffectively controlled without the assistance of antiviral drugs. Dengue virus infection leads to lasting immunity against re- infection by the same serotype, but in fact causes far more severe disease if the individual is re-infected with a different Dengue serotype than if he/she were completely nave. Similarly, influenza strains continuously alter themselves genetically; thus immunity to a given strain rarely affords complete protection against all subsequent influenza viruses that circulate in time and space. Natural infection with malaria does not necessarily lead to lasting immunity, as the same individual can be re-infected many times over the course of a lifetime. Pathogens like these thus pose a conundrum: how can vaccines designed to mimic the natural pathogen elicit immunity when the immune system is intrinsically incapable of generating broad and effective immunity when faced with the actual infection? Innovative alternate strategies, such as structure-guided sequential immunizations, gene therapy, and cell-based therapy have all been proposed, though the latter approach is the least developed. In this application, we thus focus on cell-based therapies and propose to 1) develop strategies to differentiate human pluripotent stem cells into transplantable pathogen-specific plasma cells, and 2) Use CRISPR/Cas9 genome editing to eliminate major determinants of immunogenicity from human pluripotent stem cells to allow scalable off-the-shelf therapies for infectious disease.